Cancer is a leading cause of death worldwide. In 2008, various cancers accounted for 7.6 million deaths (around 13% of all deaths), according to the World Health Organization (WHO), and this number is projected to continue rising, with an estimated 13.1 million deaths worldwide in 2030 [GLOBOCAN 2008 (IARC) Section of Cancer Information (Nov. 11, 2012)].
Malignant melanoma is responsible for a majority of deaths caused by skin tumors, and is the most common malignancy in young adults. When melanoma is metastatic, prognosis is unfavorable, and the therapeutic alternatives are few. Uveal melanoma has different clinical features than skin melanomas, and often spreads primarily to liver. For uveal melanoma it has been proposed that approximately one out of two patients will develop metastases within 15 years after treatment of the primary ocular tumor. The average survival time after diagnosis of liver metastases is 8 to 10 months and the mortality rate in patients with liver metastases of uveal melanoma is 92% over two years. One treatment option is regional perfusion of the liver with hyperthermia and melphalan. This approach is however very invasive and associated with risks of surgical complications. Even though remissions are seen in most cases, survival is only marginally prolonged.
Melanoma of the skin and uveal melanoma are merely two examples of cancer, which takes the lives of millions of people each year. Treatment of cancer is therefore one of the major challenges facing modern medicine.
In general, current anti-cancer therapeutic strategies include surgery, radiotherapy, cytotoxic drugs (chemotherapy) and hormone drugs. A drawback of chemotherapeutic agents is that they are unselective and cause adverse side effects, which effectively limits dosage and hence also the therapeutic effect. There is a need for improved, more selective cancer therapies.
A rare example of a medication directly targeted to a point mutation oncogene is vemurafenib, targeting specifically the BRAFV600E mutation common in skin melanomas, with relatively less off-target effects compared to chemotherapy. However this treatment only prolongs life with a few months in metastatic melanoma, and only works in those melanomas that have this specific mutation. A possibility would therefore be to target the downstream signaling molecules. The downstream targets however lack enzymatic activity, and are often impossible to treat with small molecules, because of their tertiary structure. Further, as a small molecule inhibitor would distribute throughout the body, it would also cause systemic side effects in normal, healthy cells that are depending on such downstream molecules.
Over the last decade, gene therapy has received increased attention and it is believed that in the future gene therapy may be applicable to many diseases, including cancer.
The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene in order to replace a mutated gene. Other types of gene therapy involve directly correcting a mutation, or using DNA that encodes a therapeutic protein drug (rather than a natural human gene) to provide treatment. It has also been suggested that RNA interference, referred to as RNAi, may be possible to exploit in gene therapy against e.g. infections or cancer.
RNAi is a gene regulating mechanism occurring in many eukaryotic cells which has been known since the late 1990's, and which has been, used primarily as a research tool to achieve gene knockout.
However, a major challenge for the development of RNAi-based therapeutics and other gene therapy applications is delivery of the therapeutic agent (e.g. an RNA molecule). Viral vectors may be efficient, but give rise to safety concerns, and can be rapidly eliminated by a patient's immune system, reducing its impact.
The mode of delivery is particularly important when the target is a gene or gene product that is important to the function also of normal healthy cells. Therefore, delivering a drug in a concentrated way to a diseased cell specifically has the potential to reduce systemic side effects and side effects in other cells.
Hence, one obstacle to successful targeting of genes and proteins involved in disease, including cancer, is the development of a safe and effective method of delivering the therapeutic agent to the target.